DE69633376T2 - Measuring device for intraocular substances - Google Patents

Description

background the invention

Territory of invention

The The present invention relates to a device for measuring intraocular substances by irradiating an eyeball with a monochromatic or single-wavelength excitation light beam in the visible to near-infrared region of an optical excitation system and by detecting measuring light which is at least either scattered Light or fluorescence generated by the eyeball be through an optical photo-receiving system.

description of the prior art

A Glass fluorophotometry (VFP = Vitreous Fluorophotometry) is used as an exam a quantitative testing of the function of a blood ocular barrier carried out, by using intraocular fluorescence as a method of irradiation of the eyeball with stimulating light and getting information measured from scattered light or fluorescence from the eyeball becomes.

Around To diagnose diabetes mellitus or the need for one To assess insulin administration, the blood sugar level must be measured become. Although a method for collecting blood for measuring the Blood sugar level is correct, this causes pain to the patient and the exam is troublesome and takes a long time.

Therefore Various methods of non-invasive measurement become intraocular Examined substances based on optical information of eyeballs. Method of irradiating eyeballs with excitation light and of measuring the blood sugar levels based on it Information is z. B. examined. Such a procedure is a method of irradiating the crystalline lens with excitation light, a receiving backscattered Light of the same, separating it in fluorescent and Rayleigh light through a spectroscope or a two-color beam splitter, a get-together of information that allows a diagnosis of diabetes mellitus, from a value obtained by normalizing the fluorescence intensity with the Rayleigh light intensity and diagnosing diabetes mellitus, cataract or another disease on this basis (ref U.S. Patent No. 5,203,328).

at Another method is infrared absorption by the crystalline lens or refractive index of visible light Get the blood sugar level in the crystalline lens on this basis measured (referring to Japanese Patent Laid-Open Publication No. Hei. 51-75498 (1976)). In yet another method, aqueous humor, this creates a void between the cornea and the crystalline lens crowded, irradiated with plan-polarized light, so that the blood sugar level by measuring the angle of rotation of the polarization axis or the refractive index is obtained (with reference to U.S. Patent No. 3,963,019).

One Method for obtaining a cholesterol value as another Vital substance is also suggested. In this process the aqueous humor is irradiated with excitation light, so that the intensity scattered light from it or the mobility of a protein that is a spreader is measured to obtain the cholesterol value (ref U.S. Patent No. 4,836,207).

In Information from glass bodies, crystalline ones, plays a role in the previously studied methods Lentils, aqueous humor etc. of the eyeballs central rollers. The inventor However, it has discovered that information from the cornea is a specific one Have property that is not information from other sections of the eyeball (reference to 19th Corneal Conference, Program, Abstracts, 122 "Influence of Blood-Sugar Level Exerted on Corneal Natural Fluorescence on Sufferer from Diabetic Retinopathy "(influence of a change in blood sugar level, exercised on a natural Corneal fluorescence in a patient with diabetes retinopathy) and the abstract of the conference "Clinical & Epidemiologic Research, Electrophysiology, Physiology & Pharmacology, Retina "(clinical and epidemiological research, electrophysiology, physiology and Pharmacology, Retina) (Nos. 2208-175)).

"Investigative Ophthalmology & Visual Science", Vol. 29, No. 8, August 1998, pages 1285 to 1293, XP 002029179, JW McLaren et al., "A Scanning Ocular Spectrofluorophotometer" (a moving ocular spectrofluorophotometer) discloses a moving ocular spectrofluorophotometer (SOSF) that moves across the cornea and anterior chamber of the eye to produce a two-dimensional cross-sectional view of the anterior segment of the eye. The SOSF shows the distribution, redistribution and disappearance of fluorophores at specific time intervals after administration (local or intraocular injection) of fluorescent dyes and fluorescently-labeled molecules. A movable scanning arrangement rotates the excitation light beam in a front / rear direction through the entire anterior segment of the eye, including those the eye chamber and the crystalline lens.

The The object of the present invention is a device for measuring various intraocular substances on the base of stray light coming from a specific region of an eyeball is created to create.

These The object is achieved by the device according to claim 1.

consequently It is an object of the present invention to provide a device to measure various intraocular substances that effective for A diagnosis of disease is by selectively providing optical information be picked up by the cornea.

The Measuring device according to the present The invention relates to an optical excitation system which is in such a Positional relationship is arranged that an excitation light beam not on a crystalline lens, but on a cornea, in one state Fixing an eyeball in a prescribed measurement position incident while the eyepiece axis is fixed in a measuring direction, and an optical one Photoreception system having an optical axis extending spatial different from an optical axis of the excitation optical system, and an optical device for guiding measuring light emitted from the cornea is generated, while the measuring light of the distinguished from other parts of the eyeball and a photodetector for detecting the measuring light, is passed through the optical device for irradiating the Cornea with the excitation light beam from the excitation optical system and for detecting measuring light generated by the cornea, through the optical photoreceptor system, thereby producing intraocular substances be measured.

The The photoreceiving optical system preferably further has a spectroscopic Device for separating the measuring light generated by the eyeball is, in its spectral components. The spectroscopic device is z. B. between the optical device for guiding the measuring light, which is produced by the cornea while distinguishing it from that which is generated by other portions of the eyeball, and provided during the photodetector the photodetector is arranged to detect the measuring light, that through the spectroscopic device into its spectral components is disconnected. When the spectroscopic device is not of the wavelength dispersion type Alternatively, the spectroscopic device can be used on one Light incident side of the aforementioned optical device arranged be.

Around to fix the eyepiece axis in a specific direction, like z. B. the direction of the optical axis of the optical photoreception system or z. B. a direction that is at a constant angle to the direction the optical axis retains, The apparatus preferably further comprises an eyepiece axis optical fixation system indicative of an eyepiece axis fixation light source for generation Light independent from the light source of the excitation optical system and for introducing a light beam from this light source into the eyeball.

The Optic eyepiece axis fixation system may alternatively be on the side of the eyeball, whose intraocular substances are measured should, or on the side of another eyeball, its intraocular Substances are not measured.

If the eyepiece axis is not fixed, it is preferred that a Measurement performed can be when the eyepiece axis in a prescribed direction is that suitable for the measurement is. Thus, a two-dimensional solid-state imaging device, such as B. a CCD solid state image pickup device, as a monitoring device for observing the direction of the eyeball to enclose a Output of the photodetector of the photoreceptive optical system while the Monitored direction of the eyeball with the two-dimensional solid state imaging device will be provided.

According to the present Invention, the excitation optical system is arranged so that the excitation light beam does not invade the crystalline lens. In the case of introducing the Excitation light beam, so that the optical axis of the optical Excitation system itself with the eyepiece axis on the cornea in one Condition of fixing the eyeball in the prescribed measuring position, while the Eyepiece axis is fixed in the measuring direction, cuts, it will preferably, the angle for cutting with the eyepiece axis to about 40 ° to To set 90 °, so that the incident light beam does not pass through the pupil on the crystalline lens is incident. The size of the pupil has an individual variation and so varies the lower Limit of about 40 ° of Winkels with the object while this is the lower limit angle for preventing the excitation light beam into the crystalline lens, means.

Both a single photoelectric conversion element and a one-dimensional solid state image pickup device, such. As a CCD sensor or a photodiode array, as well as a two-dimensional solid-state image pickup device such. B. a CCD solid-state image pickup can be used as the photodetector of the photoreceptive optical system.

If the photodetector by a one-dimensional solid state image pickup device is formed, this one-dimensional solid state image pickup device preferably arranged such that photoelectric conversion elements arranged along a straight line, which is a prescribed Angle to the optical axis of the photo-receiving optical system in a plane forming the optical axis of the excitation optical system and the optical axis of the photo-receiving optical system, making it possible is a position at which the plane containing the optical axes of the comprises optical excitation and the optical photo-receiving system, intersects with the eyeball, positions of the photoelectric Conversion elements of the one-dimensional solid-state imaging device by the optical device for guiding the measuring light emitted by the cornea is generated while the measurement light is differentiated from those of others Sections of the eyeball is generated to assign.

A Such optical device may be through a slot, a fiber optic Lens array or a lens may be formed. The slot can through a Arranging a plurality of thinner Plates having a direction parallel to the optical axis of the photoreception optical system and perpendicular to the plane, the optical axes of the optical excitation and the optical Photo-receiving system comprises, in a direction perpendicular to the optical axis of the optical photoreception system in the plane, the optical axes of the optical excitation and the photoreceptive optical system includes, implements. The fiber optic lens array, the also condenser lens array or Selfoc lens array is called, is parallelized by placing a fiber optic device the optical axis of the photo-receiving optical system in the direction perpendicular to the optical axis of the photoreceptive optical system is, in the plane, the optical axes of the optical excitation and the optical Photoreception system comprises generated. The lens is adapted a picture on the cornea in the area of the eyepiece axis on the To form photodetector.

In In this case, the spectroscopic device must be able to to separate the light into its spectral components while the Correspondence between the position on the eyeball and the positions the photoelectric conversion elements of the one-dimensional solid state image pickup device and a FT (Fourier transform spectroscope), a filter or an AOTF (acousto-optic tunable filter) may be used as one Such spectroscopic device can be used to inter mediate the one-dimensional solid-state imaging device and the optical device to be arranged.

If the photodetector through the one-dimensional solid state image pickup device is formed, it is possible the incident light of the position on the eyeball through the optical Assign device that is provided on the incidence side to to identify from which part of the eyeball the information whereby the intraocular substances were measured more correctly can be.

If the photodetector through the one-dimensional solid state image pickup device is formed and only receives light, which is generated by a point where the optical axes the optical excitation and the optical photo-receiving system It is possible to use a polychrometer to cut each other on the cornea generate simultaneously segregated multiple wavelengths can by adding a FT, an AOTF or a diffraction grating to the one-dimensional Solid-state imaging device is combined, as well as wavelength dispersion measuring light from the point in the arrangement direction of the photoelectric conversion elements the one-dimensional solid-state imaging device.

If the photodetector through a single photoelectric conversion element is formed, a photodiode may be used as the photodetector become. In this case, the optical photo-receiving system with an optical device for the exclusive insertion of Light generated by the point where the optical axes are the optical excitation and the optical photoreception system cut on the cornea, provided in the photodetector. Such optical device can through a slot, a fiber optic Lens array or a lens may be formed. A diffraction grating from Dispersion type can also be used as the spectroscopic device as well as an FT, a filter and an AOTF.

When the photodetector is constituted by a two-dimensional solid-state imaging device, the optical device of the photoreceiving optical system can position the plane at which the plane including the optical axes of the excitation optical and photoreceptive optical systems intersects the eyeball with a position on a line assign an arrangement of the photoelectric conversion element of the two-dimensional solid-state image pickup device. Such an optical device may also be formed by a slot, a fiber optic lens array or a lens. In this case, the spectroscopic means by a multi-channel spectroscope for wavelength dispersion of the light in a direction perpendicular to the array of the photoelectric conversion element, and for separating it into its spectral components, so that measuring light beams generated from a plurality of positions on the eyeball are independent in spectral components of the same can be separated and detected.

If the photodetector through the two-dimensional solid state image pickup device is formed, it may also be used as a monitoring device to observe the direction of the eyeball while that of the eyeball generated measuring light is detected serve.

Of the Excitation light beam from the excitation optical system to the Eyeball is a monochromatic or single-wavelength beam in the visible to near-infrared region. One exemplary optical excitation system, such an excitation light beam generated, has a light source of a incandescent lamp, the excitation light generated with a continuous wavelength, such as. Legs Tungsten lamp or a halogen lamp, as well as a wavelength selection device, such as As a filter for Einarbigmachen the light from the light source. When the excitation light is in a parallel beam along the optical The axis of the optical excitation system is converted, the optical excitation system further comprises a slot.

One Another exemplary optical excitation system has a laser unit for generating single-wavelength excitation light in the visible to near-infrared region as a light source. When a Semiconductor laser is used as the laser unit diverges the beam and so is a lens or slot for converting of the excitation light in a parallel beam along the optical Axis of the optical excitation system necessary. When the semiconductor laser a plurality of wavelength light components is a wavelength selection device, such as z. An optical filter for selecting light of a specific one wavelength necessary.

If received light is Raman scattered light or fluorescence and the excitation light beam is monochromatic or single wavelength light, the data processing is simplified. When the excitation light is generated from near-infrared light, the eye shows no pupil reaction and so it is not necessary administer a pupil-dilating drug, and the measurement is simplified. It is for measuring a small part of the cornea or performing an area integration useful, to convert the excitation light beam into a parallel beam.

If the excitation light beam is applied only to one point of the cornea a condenser lens may be used to condense the excitation light be provided on the cornea to the optical excitation system.

If a beam splitter on the optical axis of the excitation light beam the optical excitation system is provided and a part of the excitation light, which is picked up by the beam splitter on a part of the photoelectric Conversion elements of the photodetector or another photodetector incident so that an output of the photodetector, which receives the measuring light from the Eyeball receives, by an output of the photoelectric conversion element or of the photodetector is corrected, it is possible stray light or fluorescence even to measure correctly if a fluctuation of the excitation light is present.

The optical excitation and the optical receiving system can be integrally in a goggle structure be stored on a face can be appropriate, and the measurement in this case can easily carried out become.

These A goggle structure may further be provided with a transmission circuit be the information that includes the data that is transmitted through the optical Photoreception system are measured to an external data processor can spend. The transmission circuit to transfer the measured data can be measured by a variety of facilities, such as A wireless, wired or optical pulse device, be implemented.

The first measured intraocular substance is sugar and a determination can be made for glucose through a Raman scattering tip at 420 to 1500 cm ^-1 or 2,850 to 3,000 cm ^-1 , preferably 420 to 450 cm ^-1 , 460 to 550 cm ^-1, 750 to 800 cm ^-1, 850-940 cm ^-1, 1000-1090 cm ^-1, 1090-1170 cm ^-1, 1200 to 1300 cm ^-1, 1300-1390 cm ^-1, 1450-1500 cm ^{- 1} or 2,850 to 3,000 cm ^-1 in a shifted wavenumber of one excitation wavelength. Glucose (glucose), also called blood sugar, provides the most important information for diagnosing diabetes mellitus or detecting a transition of the state of a disease.

Another sugar can also be measured. With respect to inositol, for example, a determination by a Raman scattering tip may be at 400 to 1500 cm ^-1 or 2,900 to 3,050 cm ^-1 , preferably at 400 to 500 cm ^-1 , 700 to 900 cm ^-1 , 1,000 to 1,100 cm ^{. 1} , 1,200 to 1,500 cm ^-1 or 2,900 to 3,050 cm ^-1 in a shifted wavenumber from the excitation wavelength.

With respect to fructose, a determination by a Raman scattering peak at 550 at 1,500 cm ^-1 or 2,900 to 3,050 cm ^-1 , preferably at 550 to 620 cm ^-1 , 650 to 700 cm ^-1 , 780 to 870 cm ^-1 , 900 to 980 cm ^-1 , 1,000 to 1,150 cm ^-1 , 1,200 to 1,300 cm ^-1 , 1,400 to 1,480 cm ^-1 or 2,900 to 3,050 cm ^{-1 are performed} in a shifted wavenumber of the excitation wavelength.

With respect to galactose, determination by Raman scattering tip may be at 400 to 1500 cm ^-1 or 2,850 to 3,050 cm ^-1 , preferably 450 to 550 cm ^-1 , 630 to 900 cm ^-1 , 1,000 to 1,180 cm ^-1 , 1,200 to 1,290 cm ^-1 , 1,300 to 1,380 cm ^-1 , 1,400 to 1,500 cm ^-1 or 2,850 to 3,050 cm ^-1 in a shifted wavenumber of the excitation wavelength are performed.

With respect to sorbitol, determination by Raman scattering tip may be at 380-1,500 cm ^-1 or 2,700 to 2,960 cm ^-1 , preferably at 388 to 488 cm ^-1 , 749 to 862 cm ^-1 , 933 to 1120 cm ^-1 , 1,380 to 1,464 cm ^-1 or 2,731 to 2,960 cm ^-1 in a shifted wavenumber from the excitation wavelength.

The second measured intraocular substance is a lipid and a determination can by a spectral intensity a fluorescence spectrum from 450 to 650 nm or an integrated Value of a spectrum in a suitable wavelength range within the range with respect to lecithin (phosphatidylcholine).

The third measured intraocular substance is bilirubin, and determination can be through a Raman scattering peak at 500 to 540 cm ^-1, 670-710 cm ^-1, 900-980 cm ^-1, 1220-1300 cm ^-1, 1310-1330 cm ^{- 1} , 1400 to 1500 cm ^-1 or 1550 to 1670 cm ^-1 in a shifted wavenumber of the excitation wavelength.

The fourth measured intraocular substance is a glycated protein and a determination may be made by a spectral intensity of a Fluorescence spectrum from 640 to 850 nm or an integrated value a spectrum in a suitable wavelength range within the range with respect to glycated albumin.

The fifth Measured Intraocular Substance is an AGE (Advanced Glycated Final product). The AGE can also be measured and determined similarly become. The AGE, called a final stage product, is a product in a late one Stage of such a non-enzymatic saccharification reaction (Glycation), which is an amino group of amino acid, a peptide or protein react with a carbonyl group of a reducing sugar, and is observed as a substance related to organopathy is that results from a chronic diabetes complication.

The the sixth measured intraocular substance is saccharified crystalline. Saccharified crystals can also be measured and determined similarly become.

These Intraocular substances are substances that are present in the body. A conventional one Method for measuring fluorescence from an eyeball is after injecting fluorescein-Na into a vein. The The present invention can also be used as an apparatus for measuring such externally injected fluorescence substance can be used. To this Purpose, the seventh intraocular substance measured is an external one injected fluorescence substance, such as. B. fluorescein-Na.

If the measured intraocular substances at least two types of Substances under sugar, lipid, bilirubin, a glycated protein, an AGE, sugared crystallin, and the like peak intensities or peak ranges of Raman scattered light components shifted Wavenumbers for selected these substances are, spectral intensities a fluorescence or integrated values of suitable wavelength ranges used, so that measured values of the respective substances out obtained this plurality of measured values by a multivariate regression analysis can be.

The operation of the multivariate regression analysis is adapted to perform data analysis through multivariate regression analysis such as: B. a major component regression analysis (PCR) or a sub-method least squares (PLS method) to perform. In multivariate regression analysis, a regression analysis can be performed by using a number of spectral intensities at once, allowing for quantitative analysis with higher accuracy compared to single regression analysis. While multiple regression analysis is most commonly used, a number of samples are needed and their quantitative analysis accuracy is reduced when a correlation between spectral intensities at respective shifted wavenumbers is high. On the other hand, the PCR, which is a multivariate regression analysis, can intensify spectral intensities in a plurality of shifted wavenumber regions to major components that are irrelevant to each other and delete unnecessary noise data, thereby obtaining high quantitative analysis accuracy can. Further, the PLS method can also use data of a sample concentration in extraction of main components, whereby a high quantitative analysis accuracy similar to the PCR can be obtained. Regarding the multivariate regression analysis, refer to "Tahenryo Kaiseki" (by Kazuo Nakatani, Shinyo-Sha).

Around necessary To draw information from the spectral complexity, to different Fluctuation factors fluctuates, is a data processing by a computer amazingly helpful. A common processing method is stored in a processing software that is available in a commercially available Near-infrared device or the like is provided. As commercial available software There are unscrambers from the CAMO Company or the like. The typical Processing method is the aforementioned multiple regression analysis, PLS, principal component regression analysis or the like.

Big streams one Data processing by a multivariate regression analysis applied to the quantitative regression analysis, are (1.) the formation of a calibration model (calibration curve), (2.) the assessment of the calibration model and (3) the determination of a unknown sample.

Around to perform a calibration, it is necessary, a suitable number of samples to form a calibration curve to measure with sufficient accuracy. Obtained spectra if necessary subjected to preliminary processes. Usual preliminary processes are smoothing, distinction and normalization of the spectra, which are general processes.

The Calibration is a mathematical processing of a building up interrelated expressions between spectral data and analytical values of target characteristics, d. H. Models. The formation of models is done by a statistical technique by using analytical values of samples to form a Calibration curve and performed by spectral data.

Around an accuracy of prediction of the generated calibration curve to correctly evaluate with respect to an unknown sample will be measurement errors with respect to the unknown sample obtained by a weighting test. If the accuracy of the calibration curve is not sufficient are considered the type of processing method or parameters changed as needed, to correct the calibration curve.

A Calibration curve having sufficient accuracy is considered as a relational expression for predicting of values of target characteristics from spectral data in an analysis the unknown sample used to determine the concentration to be used for the unknown sample.

According to the present Invention are the excitation optical system and the photoreception optical system so arranged to be able to be scattered light or a Capture fluorescence from the cornea, while that of different parts of the eyeball, whereby the intraocular Substances based on optical information from the cornea can be measured and information that is useful to diagnose diabetes mellitus or another disease, etc., can be obtained non-invasively.

The previous and other tasks, features, aspects and benefits The present invention will become more apparent from the following detailed Description of the present invention taken in conjunction with the accompanying drawings be more apparent.

Short description the drawings

1 Fig. 10 is a sectional plan view schematically showing an embodiment;

2A and 2 B Fig. 3 are sectional plan views schematically showing optical devices including a fiber optic lens array and a lens instead of a slit, respectively 63 use in the embodiment;

3 Fig. 12 is a sectional plan view schematically showing another embodiment having a means for correcting a fluctuation of a light source intensity;

4 Fig. 11 is a sectional plan view showing still another embodiment which sets an angle formed by optical axes of an excitation optical system and a photoreception optical system at 90 °;

5A to 5C illustrate another embodiment that integrates optical systems into a goggle structure, and is a plan view showing an arrangement of the optical systems in the interior, a side elevation to the side of a photoreceptor optical system showing the arrangement of the optical systems in the interior, or a perspective view from the perspective of the side of the eyeball;

6 represents a Raman scattering spectrum of glucose;

7 represents a Raman scattering spectrum of inositol;

8th represents a Raman scattering spectrum of fructose;

9 represents a Raman scattering spectrum of galactose;

10 represents a Raman scattering spectrum of sorbitol;

11 represents a fluorescence spectrum of glycated albumin;

12 represents a Raman scattering spectrum of ditaurobilirubin; and

13 represents a fluorescence spectrum of lecithin.

description the preferred embodiments

1 schematically represents an embodiment. The reference numeral 2 refers to an eyeball that is a crystalline lens 6 in front of a glass body 4 and a cornea 8th is provided, which is provided at the foremost part has. A space between the crystalline lens 6 and the cornea 8th is with aqueous humor 10 filled, which is a transparent liquid. An iris 11 is between the crystalline lens 6 and the cornea 8th present and a central opening of the iris 11 is the pupil. The reference number 3 denotes an eyepiece axis.

An optical excitation system 12 has an incandescent lamp, such. As a tungsten lamp, as a light source 14 on and a lens 18 for condensing excitation light coming from the light source 14 is generated, and optical filters 20 for picking up a narrow wavelength range from the excitation light and coloring it to an optical axis 16 of the optical excitation system 12 intended. A majority in the 3 , optical filter 20 is arranged so that they can be switched in response to a desired excitation beam wavelength. An excitation light beam is passed through a slit on a narrow parallel beam with a diameter of 0.1 to 2 mm 22 that is between the optical filters 20 and the lens 18 is provided, and a plurality of slots 24 set at an output side beyond the optical filter 22 are provided.

On the other hand, an optical axis differs 31 an optical photoreception system 30 spatially from the optical axis 16 of the optical excitation system 12 and is disposed at a position coincident with the optical axis 16 of the optical excitation system 12 on the cornea 8th cuts. An angle 8th passing through the optical axes 16 and 31 the optical excitation and the optical receiving system 12 and 30 is formed, is adjusted so that no excitation light beam through the pupil to the crystalline lens 6 comes in, where, when the eyeball 2 is fixed so that the eyepiece axis 3 with the optical axis 31 the optical photoreception system 30 coincides, the angle θ 40 ° to 90 °. Referring to 1 is θ 45 °.

Around the eyepiece axis 3 to fix to the optical axis 31 the optical photoreception system 30 coincide is an optical system that is a light source 32 for generating visible light, a slot 33 for converting light from the light source into a narrow beam and a half mirror 32 for placing the jet through the slot 33 is set, on the optical axis 31 and for introducing it into the eyeball 2 has provided.

In the optical photoreception system 30 is a one-dimensional solid-state imaging device 35 , such as As a CCD sensor or a photodiode array on the optical axis 31 arranged as a photodetector. The one-dimensional solid-state imaging device 35 has a line of arrangement of a CCD photoelectric conversion element whose direction is along a straight line perpendicular to the optical axis 31 the optical photoreception system 30 in a plane that is the optical axes 16 and 31 the optical excitation and the optical photoreception system 12 and 30 includes. The pitch of the arrangement of the photoelectric conversion element of the one dimensional solid state image pickup device 35 is z. B. 125 microns.

On a light incident side of the one-dimensional solid state image pickup device 35 is a slot 36 arranged as an optical device, the measuring light coming from the cornea 8th is generated, which may differ from that generated by other eyeball sections, and the same in the one-dimensional solid-state imaging device 35 can introduce. The slot 36 by arranging a plurality of thin plates in a direction parallel to the optical axis 31 the optical photoreception system 30 and perpendicular to the plane containing the optical axes 16 and 31 the optical excitation and the optical receiving system 12 and 30 includes, in a direction perpendicular to the optical axis 31 the optical photoreception system 30 in the plane, the optical axes 16 and 31 the optical excitation and the optical photoreception system 12 and 30 includes, a position at which the plane that the optical axes 16 and 31 the optical excitation and the optical photoreception system 12 and 30 includes the eyeball 2 cuts the positions of the photoelectric conversion elements of the one-dimensional solid state image pickup device 35 to. The distance of the slot 36 preferably corresponds to the distance of the photoelectric conversion element of the one-dimensional solid-state image pickup device 35 and the depth D of the slot 36 is 5 to 30 mm.

A spectroscopic device 37 , such as A FT, a filter or an AOTF, is between the slot 36 and the one-dimensional solid-state imaging device 35 arranged so that the measuring light from the eyeball 2 can be separated into its spectral components. Alternatively, the spectroscopic device 37 , such as As an FT, a filter or an AOTF, on a Messlichteinfallsseite after the slot 36 be arranged as indicated by the reference numeral 37 ' is shown.

The operation of the embodiment 1 is described. The excitation light beam falls on the aqueous humor 10 through the cornea 8th one. Only a component of measuring light scattered light or fluorescence, from the cornea 8th and the aqueous humor 10 generated parallel to the optical axis 31 is through the slot 36 transmitted and through the spectroscopic device 37 separated into their spectral components and falls on the one-dimensional solid-state imaging device 35 one. The positions of the photoelectric conversion elements of the one-dimensional solid state image pickup device 35 correspond due to the slot 36 a measurement light generation position on the eyeball 2 so that it is possible to identify from which position the information originated. In particular, a detection signal from a CCD photoelectric conversion element comprises on the optical axis 31 Information related to the scattered light and fluorescence emitted by the cornea 8th and are important for the measurement of intraocular substances. A detection signal from a CCD photoelectric conversion element at another location includes scattered light and fluorescence from the aqueous humor 10 ,

A diffraction grating can also be called the spectroscopic device 37 be used. In the case of measuring light from a single point on the cornea 8th through the slot 36 will light that through the slot 36 is transmitted to the diffraction grating to be subjected to wavelength dispersion, and the one-dimensional solid state image pickup device 35 is disposed so that the photoelectric conversion elements are arranged in the dispersion direction, thereby defining a polychromator so that the light from the single point on the cornea 8th separated into its spectral components and simultaneously detected over a number of wavelengths.

In the case of using a two-dimensional solid-state image pickup device as a photodetector, a multi-channel spectroscope may be used as the spectroscopic device 37 be used. In this case, a line of measuring light, which corresponds to the spectroscope through the slit, corresponds 36 comes in, a position on the eyeball 2 , A wavelength dispersion is performed in a direction perpendicular to an arrangement direction of the measurement light incident on the spectroscope, whereby measurement light components from a plurality of positions on the eyeball 2 simultaneously separated into spectral components thereof and simultaneously detected over respective multiple wavelengths.

The 2A and 2 B provide further examples for replacing the slot 36 out 1 as optical devices that can distinguish measuring light generated from corneas from that produced by other eyeball sections and introduce same into photodetectors. 2A shows this using a fiber optic lens array 40 wherein the pitch of the fiber optic device also preferably equals the pitch of the photoelectric conversion element of a one-dimensional solid state imaging device 35 equivalent. 2 B shows this using a lens 42 , A picture on a cornea 8th is on a one-dimensional solid-state imaging device 35 through the lens 42 formed and measuring light generating positions on the cornea 8th and the aqueous humor are in opposite directions on the one-dimensional solid state imaging device 35 arranged.

As the photodetector of the photo-receiving optical system, the one-dimensional solid state image pickup device 35 be replaced by a photodiode, which consists of a single photoelectric conversion element.

3 FIG. 12 illustrates an embodiment having means for correcting a fluctuation of a light source intensity. A half mirror 44 is on an optical axis 16 an optical excitation system 12 arranged, so that a part of the excitation light directly on a part of the photoelectric conversion elements 35a a one-dimensional solid-state imaging device 35 incident. A detection signal from a cornea or other portion passing through a photoelectric conversion element in a wide ren section of the one-dimensional solid-state image pickup device 35 is received by a detection signal of the photoelectric conversion element 35a that receives the excitation light beam is divided and standardized, whereby a fluctuation of the light source intensity can be corrected so that a correct measured value is obtained.

Referring to 4 is the angle θ passing through the optical axes 16 and 31 the optical excitation and the optical receiving system 12 and 30 in the embodiment 1 is formed, set to 90 °. In this case, only the cornea 8th are irradiated with the excitation light beam, so that the optical photoreception system 30 only the information from the cornea 8th by an exclusive reception of the measuring light, such. Scattered light and fluorescence from the cornea 8th can receive.

The 5A . 5B and 5C Fig. 14 illustrates another embodiment incorporating the present invention in a goggle structure, is a plan view showing an arrangement of optical systems inside, a side elevation to the side of a photoreceptor optical system showing the arrangement of the optical systems in the interior, and a perspective view from the perspective of the side of the eyeball. An optical excitation system 12 and an optical photo-receiving system 30 , such as B. those in the 1 and 4 are shown in a protective eyeglass structure 50 arranged. A semiconductor laser effective for miniaturization becomes in the excitation optical system 12 used as an excitation light source. Further, the goggle structure also includes a transmission circuit for driving the light source and a photodetector, and transmitting a signal detected by the photodetector to the exterior or the like. A control part 52 comprises such a driver part or the transmission circuit.

The 6 to 13 show exemplary Raman scattering and fluorescence spectra of intraocular substances to be measured in the present invention. In each figure, the excitation light is a 632.8 nm He-Ne laser beam.

6 Figure 4 shows a Raman scattering spectrum of glucose peaking at positions of 420 to 450 cm ^-1 , 460 to 550 cm ^-1 , 750 to 800 cm ^-1 , 850 to 940 cm ^-1 , 1000 to 1090 cm ^-1 , 1090 to 1,170 cm ^-1 , 1,200 to 1,300 cm ^-1 , 1,300 to 1,390 cm ^-1 , 1,400 to 1,500 cm ^-1 and 2,850 to 3,000 cm ^-1 in shifted wavenumbers of an excitation wavelength is provided. Mean wavenumbers of these peaks are 438 cm ^-1 , 530 cm ^-1 , 776 cm ^-1 , 917 cm ^-1 , 1087 cm ^-1 , 1,103 cm ^-1 , 1,298 cm ^-1 , 1,373 cm ^-1 , 1,461 cm ^-1 and 2,907 cm ^-1 .

7 shows a Raman scattering spectrum of inositol that is shifted with peaks at positions of 400 to 500 cm ^-1 , 700 to 900 cm ^-1 , 1,000 to 1,100 cm ^-1 , 1,200 to 1,500 cm ^-1, and 2,900 to 3,050 cm ^-1 Wavelengths of the excitation wavelength is provided. Mean wavenumbers of these peaks are 443, 852 cm ^-1 , 864, 743 cm ^-1 , 1074, 37 cm ^-1 , 1468.06 cm ^-1 and 2,995.59 cm ^-1 .

8th shows a Raman scattering spectrum of fructose with peaks at positions of 550 to 620 cm ^-1 , 650 to 700 cm ^-1 , 780 to 870 cm ^-1 , 900 to 980 cm ^-1 , 1,000 to 1,150 cm ^-1 , 1,200 to 1,300 cm ^-1 , 1,400 to 1,480 cm ^-1 and 2,900 to 3,050 cm ^{-1 are provided} in shifted wavenumbers of the excitation wavelength. Mean wavenumbers of these peaks are 599, 093 cm ^-1 , 688, 482 cm ^-1 , 802.175 cm ^-1 , 963.9821 cm ^-1 , 1074.37 cm ^-1 , 1267.38 cm ^-1 , 1468.0616 cm ^{. 1} and 2,995.59 cm ^-1 .

9 shows a Raman scattering spectrum of galactose that peaks with at positions of 450 to 550 cm ^-1 , 630 to 900 cm ^-1 , 1,000 to 1,180 cm ^-1 , 1,200 to 1,290 cm ^-1 , 1,300 to 1,380 cm ^-1 , 1,400 to 1,500 cm ^-1 and 2,850 to 3,050 cm ^-1 in shifted wavenumbers of the excitation wavelength. Average wavenumbers of these peaks are 495.884 cm ^-1 , 864.743 cm ^-1 , 1062.17 cm ^-1 , 1267.38 cm ^-1 , 1362.38 cm ^-1 , 1468.06 cm ^-1 and 2,976.02 cm ^-1 .

10 Figure 4 shows a Raman scattering spectrum of sorbitol peaked at positions of 388 to 488 cm ^-1 , 749 to 862 cm ^-1 , 933 to 1120 cm ^-1 , 1380 to 1464 cm ^-1, and 2,731 to 2,960 cm ^-1 in shifted Wavelengths of the excitation wavelength is provided. Average wavenumbers of these peaks are 438 cm ^-1 , 821 cm ^-1 , 1,414 cm ^-1 , near 1,600 cm ^-1 and 2,893 cm ^-1 .

11 Figure 4 shows a fluorescence spectrum of glycated albumin having a peak at 640-850 nm. Samples of aqueous solution having concentrations of 61.6%, 33.3% and 24.8% are measured and spectral intensities increase with increasing concentrations.

12 shows a Raman scattering spectrum of ditaurobilirubin with peaks at positions of 500 to 540 cm ^-1 , 670 to 710 cm ^-1 , 900 to 980 cm ^-1 , 1220 to 1300 cm ^-1 , 1310 to 1330 cm ^-1 , 1400 to 1,500 cm ^-1 and 1,550 to 1,670 cm ^-1 in shifted wavenumbers of an excitation wavelength. Average wavenumbers of these peaks are 520 cm ^-1 , 688 cm ^-1 , 940 cm ^-1 , 1250 cm ^-1 , 1320 cm ^-1 , 1445 cm ^-1 and 1615 cm ^-1 .

13 shows a fluorescence spectrum of Lecithin, which has a peak at 450 to 650 nm.

Even though the present invention is described and illustrated in detail it is clear that the same is merely illustrative and is exemplary and should not be construed as limiting the scope of the present invention being limited only by the Diction of the attached claims limited is.

Claims (21)

A measuring device of an intraocular substance for irradiating an eyeball ( 2 ) with a monochromatic or single-wavelength excitation light beam in the visible to near-infrared region from an excitation optical system ( 12 ) and for detecting a measuring light, the at least either scattered light or fluorescence emitted by the eyeball ( 2 ), by an optical photoreception system ( 30 ), whereby an intraocular substance is measured, whereby the excitation optical system ( 12 ) a photodetector ( 35 ) for detecting the measuring light, wherein the photodetector ( 35 ) comprises a plurality of photoelectric conversion elements disposed at positions corresponding to measurement light generation positions on the eyeball, the intraocular substance measurement device having an eyepiece axis optical fixation system ( 32 . 33 . 34 ) having an eyepiece axis fixation light source ( 32 ), which differs from the light source ( 14 ) of the optical excitation system ( 12 ) for generating visible light for introducing a light beam from the eyepiece axis fixing light source (Fig. 32 ) in the eyeball ( 2 ) to the eyepiece axis ( 3 ) while at a constant angle with respect to the optical axis (FIG. 31 ) of the optical photoreceptor system ( 30 ), wherein the optical excitation system ( 12 ) is arranged in such a positional relationship that the excitation light beam is not directed to a crystalline lens ( 6 ), but on a cornea ( 8th ) in a state of fixing the eyeball ( 2 ) to a prescribed measuring position while its eyepiece axis ( 3 ) is fixed in a measuring direction, incident and the optical photoreception system ( 30 ) an optical axis ( 31 ) spatially spaced from an optical axis ( 16 ) of the optical excitation system ( 12 ), one through the optical axis ( 16 ) of the optical excitation system ( 12 ) and the optical axis ( 31 ) of the optical photoreceptor system ( 30 ) is 40 ° to 90 °, the optical photo-receiving system ( 30 ) an optical device ( 36 ) for distinguishing the measuring light generated from a point at which the optical axes of the excitation optical system ( 12 ) and the optical photo-receiving system ( 30 ) intersect each other, from that generated by other eyeball sections, and to guide the measuring light to an associated photoreceptive element of the photodetector ( 35 ) having. The intraocular substance measuring device according to claim 1, wherein said photo-receiving optical system ( 30 ) a spectroscopic device ( 37 ) for separating the measuring light emitted by the eyeball ( 2 ), has in its spectral components and the photodetector ( 35 ) is adapted to detect the measuring light emitted by the spectroscopic device ( 37 ) is separated into its spectral components. The intraocular substance measuring device according to claim 1, wherein a two-dimensional solid state image pickup device as a monitoring device for observing the direction of the eyeball (FIG. 2 ), for including an output signal of the photodetector ( 35 ) of the optical photoreceptor system ( 30 ), while the direction of the eyeball ( 2 ) is observed with the two-dimensional solid state image pickup device, is provided. The intraocular substance measuring device according to claim 1, wherein the photodetector ( 35 ) of the optical photoreceptor system ( 30 ) is a two-dimensional solid state image pickup device also used as a monitoring device for observing the direction of the eyeball. The intraocular substance measuring device according to claim 1, wherein the photodetector ( 35 ) of the optical photoreceptor system ( 30 ) is a solid state image pickup device having a plurality of photoelectric conversion elements arranged along a straight line having a prescribed angle with the optical axis (Fig. 31 ) of the optical photoreceptor system ( 30 ) in a plane which forms the optical axes ( 16 . 31 ) of the optical excitation system ( 12 ) and the photoreceiving system ( 30 ), and the optical device ( 36 ) of the optical photoreceptor system ( 30 ) a position at which the plane the eyeball ( 2 ), assigns positions of the photoelectric conversion elements of the solid-state imaging device. The intraocular substance measuring device according to claim 1, wherein the photodetector ( 35 ) of the optical photoreceptor system ( 30 ) is a single photoelectric conversion element located on the optical axis ( 31 ) of the optical photoreceptor system ( 30 ), and the optical device ( 36 ) of the optical photoemp catching system ( 30 ) is adapted to only light which is generated by a point at which the optical axis ( 16 ) of the optical excitation system ( 12 ) the optical axis ( 31 ) of the optical photoreceptor system ( 30 ) on the cornea ( 8th ) into the photodetector ( 35 ) introduce. The intraocular substance measuring device according to claim 2, wherein the spectroscopic device ( 37 ) is a Fourier transform spectroscope, a filter or an acousto-optic tunable filter. The intraocular substance measuring device according to claim 2, wherein the photodetector ( 35 ) of the optical photoreceptor system ( 30 ) is a one- or two-dimensional solid-state imaging device, wherein the optical device ( 36 ) of the optical photoreceptor system ( 30 ) is adapted to only light which is generated by a point at which the optical axis ( 16 ) of the optical excitation system ( 12 ) the optical axis ( 31 ) of the optical photoreceptor system ( 30 ) in the vicinity of the cornea ( 8th ), and the spectroscopic device ( 37 ) is a spectroscope for wavelength-dispersing the light in a direction of a photoelectric conversion element array of the solid-state imaging device. The measuring device of an intraocular substance according to claim 1, wherein the excitation light beam emitted by the excitation optical system ( 12 ) to the eyeball ( 2 ) is a parallel beam along the optical axis of the excitation optical system. The measuring device of an intraocular substance according to claim 1, wherein the excitation optical system ( 12 ) with an optical condensing system ( 18 . 22 . 24 ) for condensing the excitation light beam on the cornea ( 8th ) is provided. The intraocular substance measuring device according to claim 1, wherein a beam splitter ( 44 ) on the optical axis ( 16 ) of the excitation light beam of the excitation optical system ( 12 ) is provided and a part of the excitation light through the beam splitter ( 44 ) is taken into a partial photoelectric conversion element ( 35a ) of the photodetector ( 35 ) or another photodetector is introduced, so that an output signal of the photodetector ( 35 ), the measuring light from the eyeball ( 2 ) receives with an output signal of the partial photoelectric conversion element ( 35a ) or the other photodetector is corrected. The measuring device of an intraocular substance according to claim 1, wherein the excitation optical system ( 12 ) and the photoreceptor system ( 30 ) in a protective goggle structure ( 50 ) are mounted, which can be attached to a face. The intraocular substance measuring device according to claim 12, wherein the goggle structure (FIG. 50 ) further comprising a transmission circuit ( 52 ) for outputting information comprising data transmitted by the photoreceptor optical system ( 30 ) is provided to an external data processor. The intraocular substance measuring device according to claim 1, wherein the measured intraocular substance is sugar, wherein a determination with respect to glucose is made by a Raman scattering peak at 420 to 1500 cm ^-1 or 2850 to 3000 cm ^-1 , preferably at 420 to 450 cm ^-1 , 460 to 550 cm ^-1 , 750 to 800 cm ^-1 , 850 to 940 cm ^-1 , 1000 to 1090 cm ^-1 , 1090 to 1170 cm ^-1 , 1200 to 1300 cm ^-1 , 1300 to 1390 cm ^-1 , 1450 to 1500 cm ^-1 or 2850 to 3000 cm ^-1 in a shifted wavenumber of an excitation wavelength, wherein a determination with respect to inositol is carried out by a Raman scattering tip at 400 to 1500 cm ^-1 or 900 to 3050 cm ^-1 , preferably 400 to 500 cm ^-1 , 700 to 900 cm ^-1 , 1000 to 1100 cm ^-1 , 1200 to 1500 cm ^-1 or 2900 to 3050 cm ^-1 in a shifted wavenumber of the excitation wavelength, with a determination of fructose is carried out by a Raman scattering tip at 550 to 1500 cm ^-1 , 2900 to 3050 cm ^-1 , preferably 550 to 620 cm ^-1 , 650 to 700 cm ^-1 , 780 to 870 cm ^-1 , 900 to 980 cm ^-1 , 1000 to 1150 cm ^-1 , 1200 to 1300 cm ^-1 , 1400 to 1480 cm ^-1 or 2900 to 3050 cm ^-1 in a shifted wavelength number from the excitation wavelength, wherein a determination with respect to galactose by a Raman Cone tip is carried out at 400 to 1500 cm ^-1 or 2850 to 3050 cm ^-1 , preferably at 450 to 550 cm ^-1 , 630 to 900 cm ^-1 , 1000 to 1180 cm ^-1 , 1200 to 1290 cm ^-1 , 1300 to 1380 cm ^-1 , 400 to 1500 cm ^-1 or 2850 to 3050 cm ^-1 in a shifted wavenumber of the excitation wavelength, or a determination with respect to sorbitol by a Raman scattering peak is performed at 380 to 1500 cm ^-1 or 2700 to 2960 cm ^-1 , preferably 388 to 488 cm ^-1 , 749 to 862 cm ^{- 1} , 933 to 1120 cm ^-1 , 380 to 1464 cm ^-1 or 2731 to 2960 cm ^-1 in a shifted wavenumber of the excitation wavelength is present. The intraocular substance measuring device according to claim 1, wherein the measured intraocular substance is a lipid and a lecithin determination by a spectrum intensity of a fluorescence spectrum of 450 to 650 nm or an integrated value of a spectrum of a suitable wavelength region within the Area is performed. The intraocular substance measuring device according to claim 1, wherein the measured intraocular substance is bilirubin and a determination is made by a Raman scattering peak at 500 to 540 cm ^-1 , 670 to 710 cm ^-1 , 900 to 980 cm ^-1 , 1220 to 1300 cm ^-1 , 1310 to 1330 cm ^-1 , 1400 to 1500 cm ^-1 or 1550 to 1670 cm ^-1 in a shifted wavenumber of an excitation wavelength. The measuring device of an intraocular substance according to claim 1, where the measured intraocular substance is a glycated protein and a provision relating to glycated albumin by a spectral a fluorescence spectrum of 640 or 850 nm or an integrated value a spectrum of a suitable wavelength range within the Area is performed. The measuring device of an intraocular substance according to claim 1, in which the measured intraocular substance is an end-product AGE of a glycated protein. The measuring device of an intraocular substance according to claim 1, in which the measured intraocular substance is glycated crystalline is. The measuring device of an intraocular substance according to claim 1, in which the measured intraocular substances at least two Types of substances that are included in a group are the consists of sugar, lipid, bilirubin and glycated protein, and peak intensities or peak areas of Raman scattered light shifted wavenumbers, the for selected these substances are, spectral intensities a fluorescence or integrated values of suitable wavelength ranges be used so that measured values of respective substances from a plurality of these measured values by a multivariate Regression analysis are obtained. The measuring device of an intraocular substance according to claim 1, in which the measured intraocular substance is a fluorescence substance is that from the outside is injected.